tbuckley/cabot-search huggingface dataset:
Adenoviruses in medicine: innocuous pathogen, predator, or partner
Authors: Katelyn M. MacNeil, Mackenzie J. Dodge, Andris M. Evans, Tanner M. Tessier, Jason B. Weinberg, Joe S. Mymryk
Journal: Trends in Molecular Medicine (2022)

The consequences of human adenovirus (HAdV) infections are generally mild. However, despite the perception that HAdVs are harmless, infections can cause severe disease in certain individuals, including newborns, the immunocompromised, and those with pre-existing conditions, including respiratory or cardiac disease. In addition, HAdV outbreaks remain relatively common events and the recent emergence of more pathogenic genomic variants of various genotypes has been well documented. Coupled with evidence of zoonotic transmission, interspecies recombination, and the lack of approved AdV antivirals or widely available vaccines, HAdVs remain a threat to public health. At the same time, the detailed understanding of AdV biology garnered over nearly 7 decades of study has made this group of viruses a molecular workhorse for vaccine and gene therapy applications.
Autochthonous dengue in mainland France, 2022: geographical extension and incidence increase
Authors: Amandine Cochet, Clémentine Calba, Frédéric Jourdain, Gilda Grard, Guillaume André Durand, Anne Guinard, Harold Noël, Marie-Claire Paty, Florian Franke
Journal: Eurosurveillance (2022)

France faced an unusual situation of dengue transmission in 2022, with 65 autochthonous cases spread over nine transmission events by 21 October. This exceeded the number of cases observed during the entire period 2010 to 2021. Six of these events occurred in departments that had never experienced autochthonous dengue transmission. We provide an update of dengue surveillance data in mainland France in 2022. The multiplication of transmission events calls for continuous adaption of preparedness and response to arbovirus-related risks.
Enhanced TLR3 responsiveness in hepatitis C virus resistant women from the Irish anti-D cohort
Authors: Jamie A. Sugrue, Céline Posseme, Ziyang Tan, Christian Pou, Bruno Charbit, Vincent Bondet, Nollaig M. Bourke, Petter Brodin, Darragh Duffy, Cliona O’Farrelly
Journal: Cell Reports Medicine (2022)

Natural resistance to infection is an overlooked outcome after hepatitis C virus (HCV) exposure. Between 1977 and 1979, 1,200 Rhesus D-negative Irish women were exposed to HCV-contaminated anti-D immunoglobulin. Here, we investigate why some individuals appear to resist infection despite exposure (exposed seronegative [ESN]). We screen HCV-resistant and -susceptible donors for anti-HCV adaptive immune responses using ELISpots and VirScan to profile antibodies against all know human viruses. We perform standardized ex vivo whole blood stimulation (TruCulture) assays with antiviral ligands and assess antiviral responses using NanoString transcriptomics and Luminex proteomics. We describe an enhanced TLR3-type I interferon response in ESNs compared with seropositive women. We also identify increased inflammatory cytokine production in response to polyIC in ESNs compared with seropositive women. These enhanced responses may have contributed to innate immune protection against HCV infection in our cohort.
The X factor in neurodegeneration
Authors: Rhonda Voskuhl, Yuichiro Itoh
Journal: The Journal of Experimental Medicine (2022)

Given the aging population, it is important to better understand neurodegeneration in aging healthy people and to address the increasing incidence of neurodegenerative diseases. It is imperative to apply novel strategies to identify neuroprotective therapeutics. The study of sex differences in neurodegeneration can reveal new candidate treatment targets tailored for women and men. Sex chromosome effects on neurodegeneration remain understudied and represent a promising frontier for discovery. Here, we will review sex differences in neurodegeneration, focusing on the study of sex chromosome effects in the context of declining levels of sex hormones during aging.
Identification and interrogation of the gene regulatory network of CEBPA-double mutant acute myeloid leukemia
Authors: Assunta Adamo, Paulynn Chin, Peter Keane, Salam A. Assi, Sandeep Potluri, Sophie G. Kellaway, Daniel Coleman, Luke Ames, Anetta Ptasinska, H. Ruud Delwel, Peter N. Cockerill, Constanze Bonifer
Journal: Leukemia (2022)

Abstract Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy caused by mutations in genes encoding transcriptional and epigenetic regulators together with signaling genes. It is characterized by a disturbance of differentiation and abnormal proliferation of hematopoietic progenitors. We have previously shown that each AML subtype establishes its own core gene regulatory network (GRN), consisting of transcription factors binding to their target genes and imposing a specific gene expression pattern that is required for AML maintenance. In this study, we integrate gene expression, open chromatin and ChIP data with promoter-capture Hi-C data to define a refined core GRN common to all patients with CEBPA -double mutant ( CEBPA N/C ) AML. These mutations disrupt the structure of a major regulator of myelopoiesis. We identify the binding sites of mutated C/EBPα proteins in primary cells, we show that C/EBPα, AP-1 factors and RUNX1 colocalize and are required for AML maintenance, and we employ single cell experiments to link important network nodes to the specific differentiation trajectory from leukemic stem to blast cells. Taken together, our study provides an important resource which predicts the specific therapeutic vulnerabilities of this AML subtype in human cells.
Efficacy of a Hip Brace for Hip Displacement in Children With Cerebral Palsy
Authors: Bo Ryun Kim, Jin A. Yoon, Hyun Jung Han, Young Il Yoon, Jiwoon Lim, Seungeun Lee, Seon Cho, Yong Beom Shin, Hyun Jung Lee, Jee Hyun Suh, Joonyoung Jang, Jaewon Beom, Yulhyun Park, Jung-Hwa Choi, Ju Seok Ryu
Journal: JAMA Network Open (2022)

Importance There is no consensus on interventions to slow the progress of hip displacement in patients with cerebral palsy. Objective To investigate the efficacy of a novel hip brace in preventing progressive hip displacement in patients with cerebral palsy. Design, Setting, and Participants This 2-group randomized clinical trial was conducted at 4 tertiary hospitals in South Korea from July 2019 to November 2021. Participants included children aged 1 to 10 years with nonambulatory cerebral palsy (Gross Motor Function Classification System level IV or V). Block randomization was used to assign an equal number of patients to the study and control groups via computerized random allocation sequences. Data were analyzed from November to December 2021. Interventions The intervention group wore the hip brace for at least 12 hours a day for the study duration (ie, 12 months). Follow-up evaluations were performed after 6 and 12 months of wearing the brace. Both groups proceeded with conventional rehabilitation therapy during the trial. Main Outcomes and Measures The primary outcome was the Reimers migration index (MI) on radiography, as assessed by 3 blinded investigators. Primary outcome variables were analyzed using linear mixed models. Secondary outcomes include change in the Caregiver Priorities &amp;amp;amp; Child Health Index of Life with Disabilities, on which lower scores indicate better quality of life. Results A total of 66 patients were included, with 33 patients (mean [SD] age, 68.7 [31.6] months; 25 [75.8%] boys) randomized to the intervention group and 33 patients (mean [SD] age, 60.7 [24.9] months; 20 [60.6%] boys) randomized to the control group. The baseline mean (SD) MI was 37.4% (19.3%) in the intervention group and 30.6% (16.3%) in the control group. The mean difference of the MI between the intervention group and control group was −8.7 (95% CI, −10.2 to −7.1) percentage points at 6 months and −12.7 (95% CI, −14.7 to −10.7) percentage points at 12 months. The changes in the Caregiver Priorities &amp;amp;amp; Child Health Index of Life with Disabilities were favorable in the study group and reached statistical significance at the 6-month follow-up compared with the control group (difference, −14.2; 95% CI, −25.2 to −3.3). Conclusions and Relevance In this randomized clinical trial, the novel hip brace was significantly effective in preventing the progression of hip displacement, compared with the control group. It effectively improved quality of life in patients with nonambulatory cerebral palsy. Therefore, hip brace use could be a promising treatment method to delay hip surgery and improve the quality of life of patients with nonambulatory cerebral palsy. Trial Registration ClinicalTrials.gov Identifier: NCT04033289
In vivo PDX CRISPR/Cas9 screens reveal mutual therapeutic targets to overcome heterogeneous acquired chemo-resistance
Authors: Anna-Katharina Wirth, Lucas Wange, Sebastian Vosberg, Kai-Oliver Henrich, Christian Rausch, Erbey Özdemir, Christina M. Zeller, Daniel Richter, Tobias Feuchtinger, Markus Kaller, Heiko Hermeking, Philipp A. Greif, Daniela Senft, Vindi Jurinovic, Ehsan Bahrami, Ashok Kumar Jayavelu, Frank Westermann, Matthias Mann, Wolfgang Enard, Tobias Herold, Irmela Jeremias
Journal: Leukemia (2022)

Abstract Resistance towards cancer treatment represents a major clinical obstacle, preventing cure of cancer patients. To gain mechanistic insights, we developed a model for acquired resistance to chemotherapy by treating mice carrying patient derived xenografts (PDX) of acute lymphoblastic leukemia with widely-used cytotoxic drugs for 18 consecutive weeks. In two distinct PDX samples, tumors initially responded to treatment, until stable disease and eventually tumor re-growth evolved under therapy, at highly similar kinetics between replicate mice. Notably, replicate tumors developed different mutations in TP53 and individual sets of chromosomal alterations, suggesting independent parallel clonal evolution rather than selection, driven by a combination of stochastic and deterministic processes. Transcriptome and proteome showed shared dysregulations between replicate tumors providing putative targets to overcome resistance. In vivo CRISPR/Cas9 dropout screens in PDX revealed broad dependency on BCL2 , BRIP1 and COPS2 . Accordingly, venetoclax re-sensitized derivative tumors towards chemotherapy, despite genomic heterogeneity, demonstrating direct translatability of the approach. Hence, despite the presence of multiple resistance-associated genomic alterations, effective rescue treatment for polychemotherapy-resistant tumors can be identified using functional testing in preclinical models.
DNA sequence and chromatin modifiers cooperate to confer epigenetic bistability at imprinting control regions
Authors: Stefan Butz, Nina Schmolka, Ino D. Karemaker, Rodrigo Villaseñor, Isabel Schwarz, Silvia Domcke, Esther C. H. Uijttewaal, Julian Jude, Florian Lienert, Arnaud R. Krebs, Nathalie P. de Wagenaar, Xue Bao, Johannes Zuber, Ulrich Elling, Dirk Schübeler, Tuncay Baubec
Journal: Nature Genetics (2022)

Abstract Genomic imprinting is regulated by parental-specific DNA methylation of imprinting control regions (ICRs). Despite an identical DNA sequence, ICRs can exist in two distinct epigenetic states that are memorized throughout unlimited cell divisions and reset during germline formation. Here, we systematically study the genetic and epigenetic determinants of this epigenetic bistability. By iterative integration of ICRs and related DNA sequences to an ectopic location in the mouse genome, we first identify the DNA sequence features required for maintenance of epigenetic states in embryonic stem cells. The autonomous regulatory properties of ICRs further enabled us to create DNA-methylation-sensitive reporters and to screen for key components involved in regulating their epigenetic memory. Besides DNMT1, UHRF1 and ZFP57, we identify factors that prevent switching from methylated to unmethylated states and show that two of these candidates, ATF7IP and ZMYM2, are important for the stability of DNA and H3K9 methylation at ICRs in embryonic stem cells.
Multi-ancestry genome-wide association analyses identify novel genetic mechanisms in rheumatoid arthritis
Authors: Kazuyoshi Ishigaki, Saori Sakaue, Chikashi Terao, Yang Luo, Kyuto Sonehara, Kensuke Yamaguchi, Tiffany Amariuta, Chun Lai Too, Vincent A. Laufer, Ian C. Scott, Sebastien Viatte, Meiko Takahashi, Koichiro Ohmura, Akira Murasawa, Motomu Hashimoto, Hiromu Ito, Mohammed Hammoudeh, Samar Al Emadi, Basel K. Masri, Hussein Halabi, Humeira Badsha, Imad W. Uthman, Xin Wu, Li Lin, Ting Li, Darren Plant, Anne Barton, Gisela Orozco, Suzanne M. M. Verstappen, John Bowes, Alexander J. MacGregor, Suguru Honda, Masaru Koido, Kohei Tomizuka, Yoichiro Kamatani, Hiroaki Tanaka, Eiichi Tanaka, Akari Suzuki, Yuichi Maeda, Kenichi Yamamoto, Satoru Miyawaki, Gang Xie, Jinyi Zhang, Christopher I. Amos, Edward Keystone, Gertjan Wolbink, Irene van der Horst-Bruinsma, Jing Cui, Katherine P. Liao, Robert J. Carroll, Hye-Soon Lee, So-Young Bang, Katherine A. Siminovitch, Niek de Vries, Lars Alfredsson, Solbritt Rantapää-Dahlqvist, Elizabeth W. Karlson, Sang-Cheol Bae, Robert P. Kimberly, Jeffrey C. Edberg, Xavier Mariette, Tom Huizinga, Philippe Dieudé, Matthias Schneider, Martin Kerick, Joshua C. Denny, Koichi Matsuda, Keitaro Matsuo, Tsuneyo Mimori, Fumihiko Matsuda, Keishi Fujio, Yoshiya Tanaka, Atsushi Kumanogoh, Matthew Traylor, Cathryn M. Lewis, Stephen Eyre, Huji Xu, Richa Saxena, Thurayya Arayssi, Yuta Kochi, Katsunori Ikari, Masayoshi Harigai, Peter K. Gregersen, Kazuhiko Yamamoto, S. Louis Bridges, Leonid Padyukov, Javier Martin, Lars Klareskog, Yukinori Okada, Soumya Raychaudhuri
Journal: Nature Genetics (2022)
JMJD4-demethylated RIG-I prevents hepatic steatosis and carcinogenesis
Authors: Zhenyang Li, Ye Zhou, Kaiwei Jia, Yingyun Yang, Liyuan Zhang, Suyuan Wang, Yue Dong, Mu Wang, Yunhui Li, Shan Lu, Wannian Zhang, Luxin Zhang, Yiwen Fan, Dingji Zhang, Nan Li, Yizhi Yu, Xuetao Cao, Jin Hou
Journal: Journal of Hematology & Oncology (2022)

Hepatocarcinogenesis is driven by necroinflammation or metabolic disorders, and the underlying mechanisms remain largely elusive. We previously found that retinoic acid-inducible gene-I (RIG-I), a sensor for recognizing RNA virus in innate immune cells, is mainly expressed by parenchymal hepatocytes in the liver. However, its roles in hepatocarcinogenesis are unknown, which is intensively investigated in this study.DEN-induced necroinflammation-driven hepatocarcinogenesis and STAM NASH-hepatocarcinogenesis were carried out in hepatocyte-specific RIG-I knockout mice. The post-translational modification of RIG-I was determined by mass spectrometry, and specific antibodies against methylated lysine sites and the RIG-I lysine mutant mice were constructed to identify the functions of RIG-I methylation.We interestingly found that DEN-induced hepatocarcinogenesis was enhanced, while NASH-induced hepatocarcinogenesis was suppressed by hepatocyte-specific RIG-I deficiency. Further, IL-6 decreased RIG-I expression in HCC progenitor cells (HcPCs), which then viciously promoted IL-6 effector signaling and drove HcPCs to fully established HCC. RIG-I expression was increased by HFD, which then enhanced cholesterol synthesis and steatosis, and the in-turn NASH and NASH-induced hepatocarcinogenesis. Mechanistically, RIG-I was constitutively mono-methylated at K18 and K146, and demethylase JMJD4-mediated RIG-I demethylation suppressed IL-6-STAT3 signaling. The constitutive methylated RIG-I associated with AMPKα to inhibit HMGCR phosphorylation, thus promoting HMGCR enzymatic activity and cholesterol synthesis. Clinically, RIG-I was decreased in human hepatic precancerous dysplastic nodules while increased in NAFLD livers, which were in accordance with the data in mouse models.Decreased RIG-I in HcPCs promotes necroinflammation-induced hepatocarcinogenesis, while increased constitutive methylated RIG-I enhances steatosis and NASH-induced hepatocarcinogenesis. JMJD4-demethylated RIG-I prevents both necroinflammation and NASH-induced hepatocarcinogenesis, which provides mechanistic insight and potential target for preventing HCC.
Clinical and pathological features of cutaneous manifestations in VEXAS syndrome: A multicenter retrospective study of 59 cases
Authors: Ève Zakine, Loula Papageorgiou, Rim Bourguiba, Arsène Mekinian, Benjamin Terrier, Olivier Kosmider, Pierre Hirsch, Marie Jachiet, Sylvain Audia, Samuel Ardois, Léopold Adélaïde, Adrien Bigot, Paul Duriez, Jean-François Emile, Estibaliz Lazaro, Damien Fayard, Joris Galland, Miguel Hié, Sébastien Humbert, Alexis Jean, Marie Kostine, Valentin Lacombe, Guillaume Le Guenno, Hervé Lobbes, Nadine Magy-Bertrand, Paola Marianetti-Guingel, Alexis Mathian, Rodérau Outh, Clémence Saillard, Maxime Samson, Guillaume Vial, Jean-David Bouaziz, Philippe Moguelet, François Chasset, Z. Amoura, A. Aouba, C. Arnaud, A. Audemard-Verger, C. Bachmeyer, B. Bienvenu, P. Biscay, F. Borlot, L. Bouillet, G. Boursier, F. Carrat, T. Cluzeau, T. Comont, A. Constantin, B. de Sainte Marie, C. Deligny, C. Dieval, E. Duroyon, M. Ebbo, O. Fain, B. Faucher, P. Fenaux, S. Georgin-Lavialle, M. Gerfaud-Valentin, J. Graveleau, A.F. Guedon, T. Hanslik, M. Heiblig, V. Jachiet, Y. Jamilloux, J. Jeannel, M. Larue, F. Le Pelletier, E. Liozon, A. Meyer, T. Moulinet, M. Pha, J. Rossignol, M. Roux, M. Roux-Sauvat, L. Sailler, G. Sarrabay, M. Sebert, A. Servettaz, P. Sujobert, L. Terriou, J. Vinit, S. Vinzio, T. Weitten, L.P. Zhao
Journal: Journal of the American Academy of Dermatology (2022)
Multi‐Targeting Nano‐Systems Targeting Heterogeneous Cancer Cells for Therapeutics and Biomarker Detection
Authors: Xiao‐He Ren, Di Han, Xiao‐Yan He, Tao Guo, Xue‐Si Chen, Xuan Pang, Si‐Xue Cheng
Journal: Advanced Healthcare Materials (2022)

Abstract Cancer heterogeneity plays a vital part in cancer resistance and metastasis. To provide a reliable approach to exert a therapy action and evaluate its efficiency in heterogeneous cancer cells, a multiple targeting delivery vector composed of histone encapsulating the therapeutic or diagnostic agent, hyaluronic acid targeting CD44 overexpressed in stem tumor cells, SYL3C aptamer targeting epithelial cell adhesion molecule (EpCAM) overexpressed in epithelial cancer cells, and CL4 aptamer targeting epidermal growth factor receptor (EGFR) overexpressed in mesenchymal cancer cells, is developed. The vector can efficiently target different cancer cells and circulating tumor cells (CTCs) in the peripheral blood of patients for mucin 1 (MUC1) knockout. Furthermore, the multiple targeting vector can be used to co‐encapsulate three types of molecular beacons for probing various mRNA biomarkers at single‐cell resolution after genome editing. This study provides an efficient approach for exerting therapeutic actions in heterogeneous cancer cells and assessing the therapeutic efficacy by detection of cancer biomarkers via liquid biopsy.
New Strategy for Promoting Vascularization in Tumor Spheroids in a Microfluidic Assay
Authors: Zhengpeng Wan, Marie A. Floryan, Mark F. Coughlin, Shun Zhang, Amy X. Zhong, Sarah E. Shelton, Xun Wang, Chenguang Xu, David A. Barbie, Roger D. Kamm
Journal: Advanced Healthcare Materials (2022)

Abstract Previous studies have developed vascularized tumor spheroid models to demonstrate the impact of intravascular flow on tumor progression and treatment. However, these models have not been widely adopted so the vascularization of tumor spheroids in vitro is generally lower than vascularized tumor tissues in vivo. To improve the tumor vascularization level, a new strategy is introduced to form tumor spheroids by adding fibroblasts (FBs) sequentially to a pre‐formed tumor spheroid and demonstrate this method with tumor cell lines from kidney, lung, and ovary cancer. Tumor spheroids made with the new strategy have higher FB densities on the periphery of the tumor spheroid, which tend to enhance vascularization. The vessels close to the tumor spheroid made with this new strategy are more perfusable than the ones made with other methods. Finally, chimeric antigen receptor (CAR) T cells are perfused under continuous flow into vascularized tumor spheroids to demonstrate immunotherapy evaluation using vascularized tumor‐on‐a‐chip model. This new strategy for establishing tumor spheroids leads to increased vascularization in vitro, allowing for the examination of immune, endothelial, stromal, and tumor cell responses under static or flow conditions.
Remote working in medicine: the good, the bad, and the barriers
Authors: Jo Best
Journal: BMJ (2022)

Many doctors dream of working from home—but it has downsides as well as upsides, and there remain issues to overcome, writes Jo Best When the covid pandemic began, doctors across the UK, just like other professionals, found themselves working increasingly from home. Is flexible working here for the long term, or is the hybrid model just a pandemic phenomenon—and how does it work for doctors? Even before the pandemic, remote working in medicine had been growing, with GP appointments by telephone and video perhaps one of the more visible examples of the change. Around a third of GP appointments are now remote,1 up from 15% before the pandemic.2 Secondary care doctors are also increasingly working outside hospital settings (box 1). A 2021 Royal College of Physicians (RCP) survey of just over 1500 members found that 57% of physicians were working remotely in some capacity.3 That figure could be set to grow: the survey also found that 76% of doctors would like to work from home. Box 1 ### Remote working at GOSH: more clinical touchpoints, fewer DNAs Like most employers, Great Ormond Street Hospital for Children in London had dabbled with remote working before the covid pandemic, with a handful of subspecialties offering video consultations. But, having introduced a single patient record system back in 2019, when covid hit the UK GOSH partnered with the video conferencing company Zoom to roll out “video visits” across 5000 staff and all subspecialties in a matter of days. Laptops with webcams were rolled out to staff, while cameras were put into outpatient suites for patients. Now, although the covid threat seems to be receding, remote working has not. And, with GOSH declaring a climate emergency, remote working offers a more sustainable alternative for the hospital’s patients and staff, by reducing the need for repeated travel to and from the central London hospital. … RETURN TO TEXT
Differences in classification schemata for myelodysplastic/myeloproliferative overlap neoplasms
Authors: Mrinal M. Patnaik, Amer M. Zeidan, Eric Padron, Uwe Platzbecker, David A. Sallman, Amy E. DeZern, Rafael Bejar, Mikkael Sekeres, Justin Taylor, Richard F. Little, Jan P. Bewersdorf, Tae Kon. Kim, Nina Kim, Christopher S. Hourigan, Matteo G. Dela Porta, Maximilian Stahl, David Steensma, Mina L. Xu, Olatoyosi Odenike, Hetty Carraway, Pierre Fenaux, Aziz Nazha, Rami Komrokji, Sanam Loghavi, Zhuoer Xie, Robert Hasserjian, Michael Savona, John M. Bennett
Journal: Leukemia (2022)